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One major mechanism underlying chemotherapy and radiation therapy for treating cancer is the induction of DNA damage. Damaging DNA in the cancer cells ensures that the genome cannot be properly propagated by subsequent cell division and proliferation. DNA damage that cannot be corrected generally induces cell death.
Cancer cells, as with normal cells, have a failsafe mechanism referred to as the DNA damage checkpoint. During cell division, the DNA damage checkpoint prevents cells with damaged DNA to progress through the cell cycle and divide, until that damage is repaired. In cancer cells, the checkpoint mechanism is believed to contribute to drug resistance because it allows the cells to repair their damaged DNA and thus continue to proliferate. Accordingly, overcoming the DNA damage checkpoint is a desirable goal for cancer therapy.
Agents that inhibit the DNA damage checkpoint are believed to enhance killing of cancer cells by DNA damage, particularly for chemotherapeutic agents that induce DNA damage. Currently, the Chk1 and Wee1 kinases are considered desirable targets for the development of DNA damage checkpoint inhibiting agents that may be used in the clinic in combination with other agents or DNA-damaging radiation therapies to improve patient treatment outcomes. There is a need to identify agents that inhibit constituents of the DNA damage checkpoint pathways.